Novel 1-(2-aryl-2-adamantyl)piperazine derivatives with antiproliferative activity

•Piperazine-based aryl adamantanes showed antiproliferative activity activity and notable selectivity.•Significantly selective binding affinity for σ1-receptor (25-fold compared to σ2).•1-(2-aryl-2-adamantyl)piperazine framework offers a promising motif for antitumoral.

Novel 1-(2-aryl-2-adamantyl)piperazine derivatives have been synthesized and evaluated in vitro for their antitumor properties against HeLa cervical carcinoma, MDA MB 231 breast cancer, MIA PaCa2 pancreatic cancer, and NCI H1975 non-small cell lung cancer. The parent piperazine 6 was found to exhibit a reasonable activity toward the HeLa and MDA MB 231 tumor cell lines (IC50= 9.2 and 8.4 μΜ, respectively). Concurrent benzene ring C4-fluorination and piperidine acetylation of the piperazino NH of compound 6 resulted in the most active compound 13 of the series in both of the above cell lines (IC50=8.4 and 6.8 μΜ, respectively). Noticeably, compounds 6 and 13 exhibited a significantly low cytotoxicity level over the normal human cells HUVEC (Human Umbilical Vein Endothelial Cells) and NHDF (Normal Human Dermal Fibroblasts).

Graphical abstractNovel 1-(2-aryl-2-adamantyl)piperazine derivatives (6–15) have been synthesized and evaluated in vitro for their antitumor properties. The parent piperazine 6 showed a good activity. A combination of piperidineacetylation at the piperazino NH-group and benzene ring C4-fluorine substitution in 6 led to the most active compound 13. Both compounds, 6 and 13, displayed low cytotoxicity against the two normal human cell lines used.Figure optionsDownload full-size imageDownload as PowerPoint slide